University of Groningen
Route of Insulin Does Not Influence 25-Hydroxyvitamin D Concentrations in Type 1 Diabetes
van Dijk, Peter R; Logtenberg, Susan J J; Waanders, Femke; Groenier, Klaas H; van Goor,
Harry; Kleefstra, Nanne; Bilo, Henk J G
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Journal of the endocrine society DOI:
10.1210/js.2019-00105
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van Dijk, P. R., Logtenberg, S. J. J., Waanders, F., Groenier, K. H., van Goor, H., Kleefstra, N., & Bilo, H. J. G. (2019). Route of Insulin Does Not Influence 25-Hydroxyvitamin D Concentrations in Type 1 Diabetes: A Brief Report. Journal of the endocrine society, 3(8), 1541-1544. https://doi.org/10.1210/js.2019-00105
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Route of Insulin Does Not Influence
25-Hydroxyvitamin D Concentrations
in Type 1 Diabetes: A
Brief Report
Peter R. van Dijk,1,2 Susan J. J. Logtenberg,3 Femke Waanders,4
Klaas H. Groenier,1Harry van Goor,5Nanne Kleefstra,2,6and Henk J. G. Bilo1,2,4
1Diabetes Centre, Isala, Zwolle 8000, Netherlands;2Department of Internal Medicine, University
Medical Center Groningen, University of Groningen, Groningen 9700, Netherlands;3Department of
Internal Medicine, Diakonessenhuis, Utrecht 3582, Netherlands;4Department of Internal Medicine, Isala, Zwolle 8000, Netherlands;5Department of Pathology and Medical Biology, University Medical
Centter Groningen, University of Groningen, Groningen 9700, Netherlands; and6Medical Research Group, Langerhans, Ommen 9700 RB, Netherlands
ORCiD numbers:0000-0002-9702-6551(P. R. van Dijk).
The increased prevalence of vitamin D [25(OH)D] deficiency in type 1 diabetes mellitus (T1DM) may be related to low insulin levels in the hepatic portal venous system. In this prospective matched-control study, we demonstrate that long-term intraperitoneal insulin does not influence 25(OH)D concen-trations in patients with T1DM as compared with subcutaneous insulin administration.
Copyright © 2019 Endocrine Society
This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
Freeform/Key Words: type 1 diabetes mellitus, intraperitoneal insulin, subcutaneous insulin, implantable pump, vitamin D, PTH
Type 1 diabetes mellitus (T1DM) is associated with an increased prevalence of vitamin D deficiency [1]. As insulin influences the activity of (hepatic) 25-hydroxylase, the enzyme that converts dietary vitamin D into calcidiol [25-hydroxyvitamin D, or 25(OH)D], a lower insulin concentration in the hepatic portal vein may influence vitamin D metabolism [2–4]. With continuous intraperitoneal insulin infusion (CIPII), insulin is infused in the intraperitoneal space, where insulin is absorbed via the capillaries of the visceral peritoneum and to a large extent into the portal vein [5–7]. We hypothesized that 25(OH)D concentrations are affected by the route of insulin administration [CIPII or subcutaneous (SC)] and that CIPII results in higher concentrations of 25(OH)D as compared with SC insulin administration.
1. Patients and Methods
This study is a post hoc analysis of a multicenter investigator-initiated study with a pro-spective, observational matched case-control design. The full study design is described else-where [8]. In short, patients with T1DM, aged 18 to 70 years, HbA1c$58 mmol/mol, and/or
five or more incidents of hypoglycemia (defined as glucose concentrations,4.0 mmol/L) per week were eligible. Cases were subjects on CIPII using an implanted insulin pump (MIP Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CIPII, continuous intraperitoneal insulin infusion; CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; SC, subcutaneous; T1DM, type 1 diabetes mellitus.
Received 14 March 2019 Accepted 11 June 2019
First Published Online 17 June 2019
ISSN 2472-1972 August 2019 | Vol. 3, Iss. 8 doi: 10.1210/js.2019-00105 | Journal of the Endocrine Society | 1541–1544
2007D; Medtronic/MiniMed, Northridge, CA) for at least 4 years before inclusion in the study. The SC control group, using multiple daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII), was age- and sex-matched to the cases. Measurements were made at baseline and after 6 months. A 25(OH)D deficiency was defined as concentrations,50 nmol/L. Using a general linear model, to adjust for possible baseline differences, the difference in 25(OH)D between the CIPII and SC groups over time was analyzed. Multivariate regression analysis was performed with 25(OH)D averaged over the study period as dependent variable and the average HbA1c, calcium, PTH, total insulin plasma concentrations, and insulin mode
(CIPII or SC) as covariates. Results are expressed as mean (with SD) or median (with interquartile range) for normally distributed and nonnormally distributed data, respectively. The study protocol was registered prior to the start of the study (NCT01621308 and NL41037.075.12) and approved by the local medical ethics committee. All patients gave informed consent.
2. Results
Of the 183 patients eligible for analysis, 11 patients (3 CIPII, 7 MDI, and 1 CSII) were excluded because of insufficient blood samples and 25 patients (7 CIPII, 9 MDI, and 9 CSII) were excluded because of the use of vitamin D supplements. Subsequently, 147 patients (29 CIPII, 54 MDI, and 64 CSII) were analyzed. Of these patients, 41% were male with a mean age 49 (12) years, diabetes duration 23 (17, 35) years, BMI 26 (4) kg/m2, HbA1c of 64 (11)
mmol/mol, and a total insulin dose of 0.6 (0.5, 0.8) units/kg/d. There were no differences in baseline characteristics between the CIPII and SC group.
A 25(OH)D deficiency was present in 61 (42%) of the patients included in the analysis: 16 of these patients were treated with CIPII and 45 with SC insulin (19 MDI and 26 CSII) (P5 0.15). As presented inTable 1, concentrations of calcium, phosphate, magnesium, and PTH changed significantly during the study period within the SC treatment group, whereas they remained stable in the CIPII group. The estimated mean 25(OH)D concentration over the study period was not significantly lower in the CIPII group as compared with the SC group: 58.3 (95% CI 51.1, 65.6) vs 64.6 (95% CI 60.8, 65.6) with a mean difference of 6.3 (95% CI21.9 to 14.5) nmol/L. Except for higher alkaline phosphatase concentrations in the CIPII group, there were no other significant differences between groups. In multivariable analysis with 25(OH)D as the dependent variable, only calcium was significant [b: 43.4; SE: 8.0 (95% CI 27.5, 59.2) with R25 0.19 for the model].
Comparisons between CIPII and the MDI and CSII groups and the comparisons between included and excluded patients also revealed no differences between groups.
3. Discussion
No considerable differences between CIPII and SC insulin administration regarding 25(OH)D concentrations and related parameters were observed in the current study. Moreover, in multi-variate regression, no influence of both the route as the total daily dose of insulin on 25(OH)D concentrations was present. These findings are in contrast to those of Coletteet al. [3], who observed higher 25(OH)D, but identical 1,25(OH)2D, levels among 13 patients treated with CIPII as compared with 28 persons treated with SC insulin. The 25(OH)D concentrations among the patients treated with SC insulin in the study by Coletteet al. [3] were lower as compared with our study (;32 nmol/L vs 65 nmol/L), whereas concentrations among CIPII-treated patients were similar. Although differences in study design may account for these discrepancies, we hypothesize that the duration of insulin therapy ($4 years in the current study as compared with several months in the study by Coletteet al. [3]) may have induced adaption of 25-hydroxylase enzyme activity and thereby normalization of 25(OH)D. Because decreased bone synthesis and strength are already present early in the course T1DM, we cannot exclude that the lack of influence of long-term treatment with CIPII on vitamin D metabolism as found in this study has no clinical consequences on bone mineral density [9]. Previous experiments in rodents suggested that insulin influences (bone- and liver-derived) alkaline phosphatase concentrations [10, 11]. As such, it could be 1542 | Journal of the Endocrine Society | doi: 10.1210/js.2019-00105
Tabl e 1 . Outc omes of Para meters o f Vit amin D M e tabo lism Durin g Baseline and Las t Visi t and Change s Betwe en the CIP II an d S C Insu lin Thera py Group s CIP II Ba seline End Cha nge Within Gro up SC Base line End Change Wit hin Group Difference Between S C v s CIP II (Base line Ad justed) Calc ium, mmo l/L 2.17 2.16 2 0.01 (2 0.15, 0.13) 2.1 6 2.09 2 0.08 (2 0.15, 2 0.01) 2 0.0 4 (2 0.1 , 0.4) Album in, g/L 41.8 42.2 0.3 5 (2 2.5 1, 3.2 2) 40 .9 40.1 2 0.78 (2 2.2 8, 0.73) 2 1.48 (2 3.10, 0.15) Phos phate, mmo l/L 0.98 0.96 2 0.02 (2 0.12, 0.09) 1.0 3 0.96 2 0.07 (2 0.13, 2 0.01) 2 0.03 (2 0.03, 0.90) Alkali ne phos phatas e, U/L 78.1 78.3 0.2 (2 9.1, 9.7) 71 .8 71.6 2 0.24 (2 5.1, 4.7) 2 6.5 (2 11.8, 2 1,1 ) Mag nesium , mmo l/L 0.75 0.73 2 0.02 (2 0.07, 0.03) 0.7 5 0.72 2 0.03 (2 0.06, 2 0.01) 2 0.01 (2 0.03, 0.03) 25(OH )D, nm ol/L 51.8 64.9 13.0 (2 1.5, 27.5) 58 .5 65.9 12.3 (4.6, 19.8) 6.3 (2 1.9, 14.5) PTH , pmol /L 4.67 4.32 2 0.33 (2 1.12, 0.45) 4.8 1 4.18 2 0.63 (2 1.0 4, 0.22) 2 0.07 (2 0.45, 0.44) Dat a a re prese nted as estim ated mea n (SD), medi an (interqua rtile ran ge), or mean change (95% CI) withi n and betwee n groups.
hypothesized that the higher alkaline phosphatase concentrations among patients treated with CIPII, as compared with patients treated with SC insulin, are a result of differences of insulin concentrations in the portal vein and/or the peripheral circulation. Nevertheless, it should be emphasized that our data are unable to explain this finding. Besides the lack of information on bone mineral density, other limitations should be taken into account when interpreting the results of this study, including the nonrandomized design, small numbers, direct insulin measurements, and the lack of information on other indices of vitamin D metabolism, including 1,25(OH)2D and FGF-23. In contrast, we included parameters of vitamin D metabolism that are routinely used in clinical practice; furthermore, plasma insulin concentrations and all other measurements were made on two separate occasions.
Taken together, these findings may indicate that after long-term treatment, the route of insulin administration does not influence 25(OH)D concentrations in T1DM.
Acknowledgments
Financial Support: This work was supported by grants from the Isala Innovatie and Weten-schapsfonds (grant INNO1717) and the Zwols WetenWeten-schapsfonds Isala Klinieken. Both sources had no role in the study design, data collection, analysis, interpretation, or writing of the report.
Additional Information
Correspondence: Peter R. van Dijk, MD, PhD, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, HPA AA41, Groningen 9700 RB, Netherlands.
E-mail:p.r.van.dijk@umcg.nl.
Disclosure Summary: The authors have nothing to disclose.
Data Availability: The data sets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
References and Notes
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